ABSTRACT, Experimental and Developmental Therapeutics Program (EDT) The mission of the EDT Program is to promote, develop, and exploit mechanism-based research for improved therapy of human cancer. The objectives of EDT are: 1) To elucidate novel cancer-selective targets for development of antitumor agents; 2) To develop novel antitumor agents that are specifically directed at cancer targets; and 3) To develop preclinical and clinical studies of cancer-selective antitumor targets with associated novel biomarkers. To accomplish this, the EDT Program provides an organized, science-based conduit for translating IUSCC discoveries from the laboratory to the clinic, and to help establish appropriate preclinical models and data to facilitate clinical translation. Likewise, clinical data generate new hypotheses tested by the strong basic science foundation throughout the IUSCC. The Program themes of EDT focus on identification of novel cancer-selective pathways followed by drug and biomarker discovery to identify optimal populations for the new treatments that emanate from our basic science laboratories. The EDT Program has two themes: Theme 1: Novel cancer-selective targets and antitumor agents towards therapeutic development; and Theme 2: Mechanism-based research trials. The aims under the preclinical Theme 1 are: 1) To investigate roles of DNA repair, genetic instability and maintenance; and 2) To elucidate targets in cell signaling cascades and metabolism. Under the clinical translational Theme 2 are two aims: 1) To translate preclinical studies of epigenetics and of selective antitumor agents; and 2) To conduct mechanism-based clinical trials. The EDT Program has two highly accomplished and complementary Co-Leaders, Drs. Boothman and Pili, who lead 46 Indiana University Melvin and Bren Simon Cancer Center (IUSCC) members (35 Full and 11 Associate), including 32 basic science investigators and 14 clinical investigators from 15 Departments, to develop novel therapeutic strategies and to evaluate these approaches by conducting investigator-initiated clinical trials. The Program has a total of $8.1M in peer-reviewed funding, with $6M from the NCI and $1.3M from other NIH Institutes. The EDT Program demonstrated over a 3-fold increase in NCI-funding from $1.9M to $6M (Direct Costs) during the last grant period. Through this Program, 2,615 patients have been entered on therapeutic trials from 2013-17 (average over 500/year) of which 63% were from IITs, National Cooperative Group or external peer-reviewed studies and only 36% were from industry-sponsored trials. The average peer-reviewed funding per Full Member has increased from $168K to $232K during the past funding period. Program members were highly collaborative as highlighted by 29% Inter-programmatic, 20% intra-programmatic and 63% inter- institutional publications. EDT Program members also contributed to 429 publications, including 81 (19%) in high impact journals. This highly interactive Program has established strong partnerships with the other Programs (HHM, TMM and CPC) and has benefited greatly from support of the IUSCC through recruitment, educational venues, pilot projects such as the ?Near-Miss? Initiative and development of its Shared Resources.